Diseases caused by viruses (virus infections) occur throughout the world and represent a serious problem in medicine, in particular because of the high variability, adaptability and mutation rate of viruses. Viruses are small particles of ca. 15 to 400 nm diameter, which are not capable of replicating themselves alone, but require a host cell for this. On the basis of their host specificity, a distinction is made between viruses which infect animals (invertebrates and vertebrates), plants, bacteria or algae, fungi and protozoa. Viral infections in general are characterized by a high reproduction rate of the viral particles in the affected host cells, which can be described by an exponential or power law. The reproductive cycle of viruses takes place via the injection of their nucleic acid (viral RNA or viral DNA) into the host cell, in which the replication of the nucleic acid takes place by utilization of the replication apparatus of the host cell. Here a distinction is made between the lytic and the lysogenic cycle. In the lytic cycle (active infection), after the injection of the nucleic acid the replication of the viral nucleic acid takes place in the cell nucleus of the host cell, and assembly of the new viral particles in the cytoplasm, after which the host cell is finally lysed (destroyed) and the viruses are released. The viruses thus released infect further host cells. In the lysogenic cycle, the nucleic acid of the virus is integrated into the genome of the host cell, where it at first remains without destroying the host cell. Due to external influences (e.g. UV radiation, addition of mutagenic substances) this lysogenic cycle can change into an aforesaid lytic cycle. In the case of RNA viruses, after infection therewith a transcription of the RNA into DNA is necessary so that replication via the host cell can take place. This process takes place via reverse transcriptase, an enzyme which is encoded by viral genes and must first be synthesized in the host cell in order to transcribe the viral RNA into viral DNA which is then in turn replicated by the DNA polymerase of the host cell.
Viruses are capable of infecting a broad spectrum of cells, organs and hosts. Each viral species specifically infects preferred cells, such as for example cells of the stomach, intestine, the skin and the respiratory tract. This leads to many so-called virus-based diseases.
Among these, virus-based diseases of the respiratory tract are a widespread and major pathological problem in medicine, in particular in man. At a percentage level of 90%, infection by viruses is the commonest cause of respiratory diseases that are caused by pathogens such as viruses and bacteria. Viruses which cause such virus-based diseases of the respiratory tract include in particular influenza viruses, parainfluenza viruses, respiratory syncytial viruses, coronaviruses, rhinoviruses, Coxsackieviruses, echoviruses, herpes viruses, human metapneumoviruses and adenoviruses, but are not limited to these.
In general, the organs affected are primarily the nose, nasal sinuses, oral cavity, tonsils, pharynx, trachea, bronchi and lung. Depending on the virus type and the severity of the infection, the viruses can affect limited areas of the respiratory tract locally or else spread to several areas. Secondarily, the ear, in particular the middle ear and the Eustachian tubes, can be affected by the viral infection.
As a rule, the viruses first infect epithelial cells, such as for example dermal, mucous and mucous membrane cells of the upper and/or lower respiratory tract, such as for example epithelial cells in the mouth, nose and pharynx and epithelial cells of the bronchioli, alveoli and trachea of the lung, followed by intense reproduction of the virus in the host cell and death of the infected host cell. The host reacts with an immune response which leads to various symptomatic syndromes. For example, the spreading of rhino-viruses takes place mainly in the epithelial cells of the mouth and nose and causes a local infection there by cold or flu symptoms such as rhinitis (head cold).
Virus-based diseases of the respiratory tract also include for example acute or chronic rhinitis, (acute or chronic nasal mucous membrane inflammation), pharyngitis, herpangina, angina lateralis, tonsillitis, laryngitis, tracheitis, acute bronchiolitis, acute bronchitis, aveolitis and pneumonia. Other diseases, such as for example acute or chronic sinusitis (acute or chronic nasal sinus inflammation), gingiovastomatitis herpetica (also known as stomatitis aphthosa, somatis herpetica) (inflammation of the oral mucous membrane and the gums), aphtosis herpetica, herpes nasalis, acute asthma, COPD (chronic obstructive pulmonary disease) and laryngeal diphtheria, which according to the invention are also among the virus-based diseases of the respiratory tract, can be triggered or intensified. The simultaneous onset e.g. of rhinitis and sinusitis (called rhinosinusitis) or of laryngitis, tracheitis and bronchitis (called laryngo-tracheo-bronchitis), or consecutive onset (successive onset) of several of these aforesaid diseases is common. Secondary diseases of the respiratory tract include for example middle ear inflammation (otitis media) and/or inflammation of the Eustachian tubes, which according to the invention are also virus-based diseases of the respiratory tract.
The symptoms and thus the syndrome which is caused by viral infections of the respiratory tract are very similar for most viruses. Nonetheless some diseases are caused preferentially by a specific viral type (see below). Further, the symptoms of the infection depend on the severity of the infection and the immune defenses of the host. By way of example, some such specific viruses, their infection route and pathological manifestation are explained in more detail below.
Infection Due to Rhinoviruses
Rhinoviruses are small, envelope-free RNA viruses of the Picornavirus group, which infect the upper and lower areas of the respiratory tract of the host, in particular of a mammal such as for example man (human pathogenic rhinoviruses or human rhinoviruses, 117 serotypes known), cattle (bovine rhinoviruses), monkeys and ferrets.
The replication of the human rhinoviruses takes place in the epithelial cells of the upper region of the respiratory tract, particularly in the epithelial cells of the pharynx, mouth and nose, wherein they bind to a cell receptor, the ICAM-1 receptor or the LDL receptor, inject their RNA into the host cell and then reproduce via the lytic cycle. The strongly site-specific replication of the virus is connected with its sensitivity to low pH values such as for example occur in the gastrointestinal tract, and high temperatures (temperature optimum: 32° C.-33° C.). In regions which lie further in the interior of the body, e.g. the lung, the virus is only rarely, and slowly, replicated on account of the physiological temperature of 37° C. prevailing there.
The diseases caused by human rhinoviruses mainly include diseases of the upper respiratory tract, in particular rhinitis and pharyngitis, and acute bronchitis. These diseases often lead to secondary infections, e.g. sinusitis (nasal sinus inflammation) and otitis media (infection of the middle ear). Less commonly, diseases of the lower respiratory tract such as for example acute asthma and COPD are triggered by rhinovirus infections. Rhinoviruses are the cause of ca. 40%-50% of all colds and flu and of ca. 34% of all respiratory infectious diseases.
Infection Due to Influenza Viruses
Influenza virus are membrane-coated RNA viruses and belong to the Orthomyxidae group. They infect both mammals, in particular man, dogs, horses, pigs and the like, and birds. The strains influenza A and influenza B are pathogenic in humans. Transmission occurs via droplets and/or direct contact.
The replication of the viruses takes place in the epithelial cells of the upper and lower respiratory tract, but particularly in the epithelial cells of the upper and lower trachea, the bronchi and the aveoli of the lung. Their reproduction takes place by the lytic cycle.
Influenza viruses lead to the pathological manifestation of what is generally termed flu. Mild infections induce colds and flu, such as rhinitis and pharyngitis, accompanied by cough, shivering, headaches, weakness and fever. Severe influenza infections affect the upper and also the lower regions of the respiratory tract and trigger diseases such as for example pharyngitis, tracheobronchitis, acute bronchitis, bronchiolitis and also less commonly and in particularly severe cases pneumonia. Infections with influenza A can even take a fatal course.
Infection Due to Parainfluenza Viruses
Parainfluenza viruses are membrane-coated RNA viruses of medium size, belong to the Paramyxoviridae group and can be transmitted via droplets and/or direct contact. They infect mammals in particular, such as man. Strains pathological to humans, which affect (infect) the respiratory system in man, in particular small children, children, immunosuppressed and elderly people, are the human parainfluenza virus 1, human parainfluenza virus 2 and human parainfluenza virus 3. They are also called respiroviruses.
Parainfluenza viruses reproduce optimally at physiological pH (pH 7.4-pH 8) and temperatures of up to 37° C. They infect epithelial cells of the upper and lower respiratory tract and reproduce via the lytic cycle.
In man, parainfluenza virus 1, parainfluenza virus 2 and parainfluenza virus 3 cause mild infections with cold and flu symptoms which resemble those of rhinitis, pharyngitis and acute bronchitis, and also severe infections, in particular laryngo-tracheo-bronchitis, tracheo-bronchitis, bronchiolitis and pneumonia. They are the main cause of laryngitis subglottica.
Infections Due to Respiratory Syncytial Virus (RSV)
The respiratory syncytial virus (RSV) is a membrane-coated RNA virus which is transmitted via droplets and/or direct infection. Both strains pathogenic in man and strains pathogenic in animals are known.
The replication of the RSV takes place firstly in the naso-pharynx, during which the RSV binds to glycosaminoglycans of surface epithelial cells and injects its RNA into the host cell. In severe infections, the viruses can penetrate into the lower part of the respiratory tract and reproduce there, particularly in the epithelial cells of the bronchioli and aveoli, via the lytic cycle.
An infection due to RSV firstly causes symptoms which resemble those of rhinitis and pharyingitis in the upper respiratory tract, accompanied by slight fever and cough. Infection of the lower respiratory tract is common and it gives rise to pathogenic manifestations such as for example tracheitis, bronchitis and bronchiolitis. Less common pathogenic manifestations are pneumonia, laryngeal diphtheria and, as a secondary disease, middle ear inflammation.
Infections Due to Herpes Viruses
Herpes viruses are widespread in vertebrates, particularly in mammals, and above all in man, horses, pigs, cattle, goats, sheep, cats and dogs. Herpes viruses pathogenic in man (HHV) are classified into alpha, beta and gamma herpes viruses (HHV-1 to HHV-8), with viruses which can infect animals such as for example horses (equine herpes virus), cattle (bovine herpes virus), pigs (porcine herpes virus), cats (feline herpes virus), dogs (canine herpes virus) and chickens (chicken herpes virus 1) belonging to the alpha and gamma viruses.
Among the herpes viruses pathogenic in man, i.e. affecting people, the alpha herpes viruses in particular are of major importance. Herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) and varicella zoster virus (VZV) are numbered among the alpha herpes viruses.
Human alpha herpes viruses as a rule firstly replicate in epithelial cells in the oral and nasal region. Further, the viruses released infect certain nerve cells (neurons) by binding to receptors of the nerve ends in the mouth, which lead to the ganglia of the facial nerve (trigeminus). The viral DNA penetrates into an axon, and is transported into the cytoplasm of the nerve cells and finally into the cell nucleus thereof. There the incorporation of the viral DNA into the genome of the nerve cell takes place and leads to a resting state (latency) in which only a few viral genes are expressed (lysogenic cycle). Various external stimuli can lead to renewed activation of the virus, the final result whereof is the destruction (lysis) of the nerve cell. The viral progeny arising during an activation are firstly transported through the axon to the site or into the region of the original infection and there once again infect epithelial cells.
HSV-1 can cause diseases of the respiratory tract, in particular in the region of the mouth. These for example include herpes nasalis, aphtosis herpetica and gigiovastitis herpetica. Furthermore, HSV infections can also lead to pneumonia.
Infections Due to Coronaviruses
Coronaviruses are membrane-coated RNA viruses which infect vertebrates, in particular mammals such as man, dogs, cats, cattle, pigs and some rodents, and birds. Coronaviruses are transmitted by droplet infection.
Among the strains pathogenic in man, human coronavirus (HCo) 229E, HCo-OC43, HCoV-NL63 and SARS infect the epithelial cells of the respiratory tract in man, in particular the upper respiratory tract. Reproduction takes place via the lytic cycle.
The diseases caused by human coronaviruses include rhinitis and pharyngitis. In addition, acute bronchitis, bronchiolitis, pneumonia, SARS (severe respiratory syndrome) and laryngeal diphtheria can be triggered. However, these diseases occur more rarely.
Infections due to human coronaviruses HCo-229E and HCo-OC43 are the cause of ca. one third of all colds and flu in man.
Infection Due to Adenoviruses
Adenoviruses are DNA viruses which infect both animals and man. Of a total of 19 species, 6 adenoviruses pathogenic in man are known (human adenoviruses A to F).
Adenoviruses are characterized by high pH and temperature stability. As a rule they enter the body via the respiratory tract. The reproduction of the adenoviruses is not restricted in location to one region. They can infect epithelial cells of the pharynx, the gastrointestinal tract and the conjunctiva. They reproduce via the lytic cycle.
An infection with adenoviruses leads to cold and flu symptoms which resemble those of rhinitis, pharyngitis, acute bronchitis and/or bronchiolitis.
Infection Due to Enteroviruses
Infections of the respiratory tract can also occur because of enteroviruses such as for example Coxsackie virus 1, Coxsackie virus 2 and echoviruses. Enteroviruses are very acid-stable RNA viruses, which are mainly transmitted fecal-orally and more rarely via droplet infections.
The reproduction of the enteroviruses as a rule begins via an infection of the cells of the small intestine tonsils. From there, the viruses migrate out to the target organs, e.g. the nose, via the bloodstream and lymph. Less commonly, enteroviruses first infect epithelial cells of the mucous membranes of the respiratory tract and reach the intestine from there. The reproduction takes place via the lytic cycle.
Enteroviruses can trigger non-specific, mild infections of the respiratory tract and pharyngo-tonsilitis, bronchiolitis, pneumonia, herpangina, hemorrhagic conjunctivitis and otitis media. Further, infections with enteroviruses cause a large number of further systemic diseases such as for example foot and mouth disease.
Most virus-based diseases of the respiratory tract can at present only be treated symptomatically. Here there are various active substances, for example alpha sympathomimetic agents, anticholinergics, antihistamines, immunosuppressants, and secretolytic agents. Through the administration of such substances, the symptoms, e.g. swellings of the mucous membranes, can be eased. Here the nature and duration of the treatment depends on the pathological manifestation and the severity of the disease. Some of these active substances and their mechanism of action are explained below; however, the enumeration should be understood to be by way of example and not exclusive:                Alpha sympathomimetic agents are alpha adrenergic antagonists which bind to alpha adrenoreceptors in the mucous membranes of the respiratory tract and thus have a stimulant effect on the sympathetic system. Through the stimulation or excitation of the sympathetic system, the vessels of the mucous membranes are narrowed. For this reason, alpha sympathomimetic agents are used for decreasing swelling of the nasal mucous membranes in colds and flu in general, and in particular for the treatment of rhinitis and sinusitis. They are administered topically in the form of nasal sprays or nasal drops. Examples of active substances are naphazoline, tetrazoline, xylometazoline, oxymetazoline and phenylephrine.        Antihistamines primarily have an anti-inflammatory action, in that they inhibit or block histamine receptors in the cells of the skin and mucous membranes of the respiratory tract, whereby the secretion of the inflammation mediator histamine is suppressed. Since the secretion of histamine mainly has a pathological role in allergic reactions, antihistamines are in particular used for the treatment of allergies. However, some antihistamines, which are called first generation H1 antihistamines, also bind to muscarinic receptors in said mucous membranes, resulting in excitation of the sympathetic system, similarly to the sympathomimetic agent. Inter alia, this secondary effect leads to a decrease in the swelling of the mucous membranes and to suppression of bronchial secretion. Antihistamines can be administered both topically and orally. Examples are diphenhydramine, tripolidine and chlorpheniramine.        Immunosuppressants are pharmaceuticals which suppress the immune response of the host and thus have an inflammation-inhibiting action. They include for example gluco-corticoids, cytostatics and (chimeric) antibodies.        Secretolytic agents are substances, such as for example salt water, camomile and sage, which are administered topically and result in the outflow of for example blocked nasal secretions in rhinitis and sinusitis.        
All the treatment approaches described above are exclusively based on a therapy of the symptoms and hence the consequences of a viral infection of the respiratory tract. None of these treatment approaches is based on a prophylactic or therapeutic action which already sets in during the viral infection or the direct consequences of an infection with a virus, and limits or blocks, preferably prevents, the outbreak of the disease, i.e. an antiviral action. In the sense of this invention, “antiviral action” should be understood in general as blocking or inhibition of the infection, replication and/or reproduction of a virus. “Replication” in the sense of the invention should be understood to mean the multiplication of the nucleic acid, both DNA and also RNA, of a virus. “Reproduction”, “reproduction of the virus” or “viral reproduction” should also be understood to mean the replication as defined above, and furthermore all processes which lead to an intact virus, such as the processing of a synthesized long viral protein into small protein segments and the assembly of the viral particles, such as for example the nucleocapsids.
Furthermore, for the said treatment approaches considerable side-effects are reported in the literature, such as for example rhinitis medicamentosus with treatment with alpha sympathomimetic agents, dermal atrophy with treatment with glucocorticoids, Cushing syndrome and adrenal cortex atrophy with long-term, systemic administration of glucocorticoids and severe exhaustion with histamine treatment.
Hence one important approach for the prophylaxis and/or therapy of virus-based diseases of the respiratory tract is the development of antiviral active substances. The aim is to intervene in the infection, replication and/or reproductive cycle of a virus, for example by inhibiting or blocking the viral infection of a host cell, the replication of the viral nucleic acid, the expression of the viral proteins encoded by the viral nucleic acid, the reproduction of the virus in the host cell and/or the release of the virus from the host cell, e.g. by budding.
However, at present a treatment of virus-based diseases of the respiratory tract with antiviral active substances is only known for infection by some viruses. Furthermore, these active substances have considerable disadvantages in that they cause undesired side-effects. Different mechanisms of action of such antiviral active substances, also called virustatics or virostatics, are described in more detail below.
For the treatment of infections due to influenza virus A and influenza virus B, neuramidase inhibitors such as zanamivir (Relenza®) and oseltamivir (Tamiflu®) are known. The enzyme neuramidase inhibited by these active substances helps newly formed viruses to bud off from the host cell. After the budding, they can then infect further host cells. Through the inhibition of the neuramidase, infection of further host cells should be avoided (Snell N J C, New treatments for viral respiratory tract infections—opportunities and problems, Journal of Antimicrobial Chemotherapy, 2001, Vol. 47, 251-259; Sugrue R I et al., Antiviral drugs for the Control of Pandemic Influenza Virus, Annals Academy of Medicine, 2008, Vol. 37, 518-524).
Further, for the treatment of infections due to influenza virus A, M2 channel blockers (amantadine, rimantadine) are known. These prevent the “uncoating”, i.e. the release of the viral nucleocapsids into the cytoplasm of the host cell (Snell N J C, New treatments for viral respiratory tract infections—opportunities and problems, Journal of Antimicrobial Chemotherapy, 2001, Vol. 47, 251-259; Sugrue R I et al., Antiviral drugs for the Control of Pandemic Influenza Virus, Annals Academy of Medicine, 2008, Vol. 37, 518-524).
For the treatment of infections due to rhinoviruses or enteroviruses, the administration of intranasal interferon and of immune serum globulin is known (Rotbart A, Hayden F G, Picornavirus Infections A primer for the practitioner, Arch Fam Med. 2000, Vol. 9, 913-920).
Furthermore, virostatic agents have been developed which block or inhibit enzymes such as for example DNA polymerase, reverse transcriptase or proteases and thus block or inhibit the replication of the virus or the processing of a synthesized long viral protein into small protein segments. Examples of such therapeutic approaches are found in particular in the therapy of HIV infections. However virostatic agents which are administered systemically or topically are also known in the field of the therapy of virus-based diseases of the respiratory tract. Examples of these are the active substances ribavirin (Flumadin®), aciclovir, valaciclovir, foscarnet and peniclovir.
For the treatment of infections due to respiratory syncytial viruses (RSV) or enteroviruses and severe bronchiopulmonary diseases triggered thereby, the inhalation of ribavirin (Flumadin®) is known (Snell N J C, New treatments for viral respiratory tract infections—opportunities and problems, Journal of Antimicrobial Chemotherapy, 2001, Vol. 47, 251-259). Ribavirin is a nucleoside analog which is integrated into the RNA of the virus and thus blocks the RNA polymerase. This results in chain termination and hence the stoppage of RNA replication and viral reproduction.
For the treatment of infections due to herpes viruses such as HSV-1, HSV-2 and VZV, orally or topically administered virostatic agents such as aciclovir, valaciclovir, foscarnet and penciclovir can be used.
For the administration of the virostatic agents described for the treatment of virus-based diseases of the respiratory tract, two approaches are known:                systemic administration: through systemic administration of virostatic agents, a significant decrease in the activation of viruses present in host cells can be achieved, since the active substances block or inhibit the reproduction of the viral nucleic acid in the cell nucleus or the assembly of the viral particles into complete viruses in the cytoplasm of the host cells;        topical administration: through topical administration of virostatic agents, for example via a nasal spray (aerosol) or nasal drops, in the region of the respiratory tract, e.g. the nose, for a first infection by the virus, the further path of the reproduction of the viruses can be prevented at an early stage, which can lead to a faster decrease in the swelling of the mucous membranes.        
However, both approaches for the administration of such virostatic agents have serious disadvantages:                with systemic administration, the dose necessary for an effective treatment is relatively high and associated with severe side-effects for the organism treated, such as for example nonspecific immune responses and autoimmune reactions. In the case of aciclovir, many such side-effects are known from the literature. Hence neither long-term nor repeated therapies are advisable nor should they be asked of a patient;        with topical administration, the quantity of active substance (virostatic agent) which can be released and become bioavailable in the region of the viral infection per unit time is very small. This low bioavailability of the virostatic agent is a considerable obstacle to an effective topical therapy. In the case of the only poorly water-soluble aciclovir, for example, the low bioavailability is due to the poor percutaneous transportation of the active substance. Various chemical modifications of virostatic agents in the context of prodrug designs for improved virostatic agent active substance input have also not led to any improvement in this phenomenon.        
Further serious disadvantages are that the antiviral options described for the therapy of virus-based diseases of the respiratory tract can lead to further considerable side-effects and can, as for example in the case of M2 channel blockers, lead to resistant viral strains which excludes treatment of diseases of this kind with such active substances and possible even further active substances for the future.
Moreover, known virostatic agents are very specific and only effective for one or a few viral species. Since however in most infections of the respiratory tract no symptomatic distinction is possible which allows a distinction to be made between the infecting viruses, a successful therapy of a virus-based disease of the respiratory tract cannot be guaranteed for many viruses on account of this high specificity of the known virostatic agents.
The only alternatives to known antiviral active substances for the prophylaxis and/or therapy of virus-based diseases of the respiratory tract which overcome the disadvantages known in the state of the art are vaccinations against the relevant viruses. However, vaccinations against viruses which infect the respiratory tract are in the present state of the art only possible for the influenza viruses (A and B) and RSV (Snell N J C, New treatments for viral respiratory tract infections—opportunities and problems, Journal of Antimicrobial Chemotherapy, 2001, Vol. 47, 251-259). Since moreover the viruses are subject to constant mutations, vaccines must always be newly developed. Hence therapies of virally caused diseases cannot be replaced by vaccinations.
There are no other alternatives to the antiviral active substances or virostatic agents disclosed in the state of the art for the prophylaxis and/or therapy of virus-based diseases of the respiratory tract which overcome the disadvantages known in the state of the art.
There is therefore a need to develop improved and more tolerable antiviral active substances which intervene in the replication and/or reproductive cycle of the virus and which preferably already block or inhibit the viral infection of the host cell.
In addition, there is a need to identify antiviral active substances which inhibit the infection, replication and/or reproduction of different viral strains or viral species simultaneously. This is particularly important since with most diseases of the respiratory tract no symptomatic distinction can be made between the various viral strains or viral species which have triggered the infection.